By Turna Ray
As it takes steps to lift its three-decade long practice of "enforcement discretion" over laboratory-developed tests, the US Food and Drug Administration shouldn't place overly burdensome requirements on laboratories that are not used to navigating the agency's regulatory landscape, representatives from the lab testing industry told the agency at a meeting last week.
The two-day meeting held by the agency in Hyattsville, Md., drew comments from numerous LDT developers and in vitro diagnostic companies, each side presenting their views on the current bifurcated regulatory pathway and FDA's stated intent to regulate all LDTs.
Traditionally, the laboratories that develop and perform LDTs have been overseen by the Centers for Medicare & Medicaid Services, but the clinical validity of these so-called "homebrew" tests is not regulated by FDA or CMS. Meanwhile, the FDA has restricted its oversight to medical device kits developed by test manufacturers, certain high-risk LDTs, and analyte-specific reagents. This piecemeal regulatory approach has created much confusion and controversy among industry players.
At the meeting, LDT developers expressed concern about having to meet divergent quality system requirements for both CMS and FDA, while some speakers questioned whether labs could meet FDA's good manufacturing practices for test development.
"Since clinical laboratories are not traditional device manufacturers, applying a strict paradigm based upon the regulation of traditional medical devices to all LDTs will have a major consequence to all clinical laboratories," David Mongillo, VP for policy and medical affairs at the American Clinical Laboratory Association, said at the FDA meeting. Such a paradigm "will place those labs in jeopardy of being unable to comply and in many cases [being] unable to continue the important work in the development of cutting-edge LDTs."
He added that the agency may need to "grandfather the vast majority of accepted and well-understood tests already in clinical use."
Still others noted that many labs already feel burdened by a complex regulatory system that includes certification from CMS' Clinical Laboratory Improvement Amendments as well as additional certification through the College of American Pathology and individual states. The New York Department of Health, which requires labs to ensure clinical and analytical validation of tests performed in the state, is considered even more stringent than CMS oversight.
"The New York State process can take over a year, and will the additional FDA oversight add additional value to that?," asked Victoria Pratt, chief director of molecular diagnostics at Quest Diagnostics' Nichols Institute.
Meanwhile, IVD manufacturers, particularly those firms that have already invested in gaining FDA clearance or approval for their tests, applauded the agency for moving toward a more equitable regulatory scheme based on the test's risk of harm to patients in the case of an incorrect result, and not based on where the test was developed.
Although the FDA has said it's pursuing a risk-based approach to regulating LDTs, the agency has provided little insight into how its existing three-tiered risk classification system for medical devices would change to include LDTs, other than to say some tests would be down-classified in risk status while other unregulated tests will have to meet submission requirements for conferring higher risk. Companies interviewed for this article did not venture to guess where FDA's LDT regulations will ultimately fall.
Bernard Sixt, CEO of Agendia, a company headquartered in Amsterdam that has cleared its MammaPrint breast cancer recurrence test through the FDA, told attendees that although the company could have taken the least burdensome regulatory pathway through CLIA, it chose to submit the test to the FDA for clearance as an in vitro diagnostic multivariate index assay "in the name of patient safety." Agendia backed a Citizen Petition submitted by Genentech in 2008, which laid out an argument in favor of FDA extending oversight to all predictive genetic tests, whether LDTs or IVDs (PGx Reporter 12/17/08).
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Recounting his firm's experience in getting FDA clearance, Sixt challenged the commonly held view that getting FDA approval for tests delays market entry and is overly burdensome. "Agendia submitted its data to the FDA and clearance came quickly and affordably," Sixt said. "In fact, in the past three years we have successfully secured four FDA clearances around MammaPrint by simply providing all our data supporting our claims." In each case, he said, the company obtained FDA clearance in less than five months.
"Stated simply, if you have good data, FDA clearance is straightforward and quick," Sixt said.
He went on to point out that Agendia has competitors in the breast cancer recurrence space who have chosen to launch tests through CMS and not go through FDA, though he didn't identify those firms by name. "Nobody will disagree that bad tests need to be taken off the market," Sixt said. "But what is incomprehensible to us is that serious industrial players still resist independent validation of widely commercialized tests."
The uneven playing field created by FDA's practice of enforcement discretion is something the agency itself has recognized. According to FDA officials who spoke at the meeting, the agency's decision to regulate all LDTs came because LDT developers were increasingly operating like IVD manufacturers. Furthermore, the FDA recognized that the marketing practices of LDT developers expanded access to a larger patient population, thereby increasing the risk of these tests to public health.
To discuss the various issues under consideration, the FDA also convened a panel of experts at the meeting, who agreed that whatever form the agency's regulation takes, there should be a strong focus on ensuring the clinical and analytical validity of LDTs.
According to FDA officials, some strategies the agency is considering in terms of its overall regulatory framework include downgrading in risk classification certain regulated tests; phasing in regulation of LDTs of currently unregulated tests; collaborating with the National Institutes of Health to develop a test registry that could serve FDA's purposes for keeping an eye on all test developers; and possibly enlisting the help of third-party inspectors to help the agency with its increasing regulatory burden.
Alberto Gutierrez, director of FDA's Office of In Vitro Diagnostic Device Evaluation and Safety, said at the meeting that the agency did not intend to issue a notice of rulemaking and comment on its LDT regulatory approach. This means the agency will likely issue guidelines for LDT development.
However at the meeting several presenters took issue with this. Anna Longwell, a lawyer who said she represented clients that were LDT developers and IVD manufacturers, noted that the confusion about the agency's LDT regulation can best be ameliorated through formal rulemaking. "Give us a rule please," Longwell asked the agency.
Diagnostic manufacturers, in turn, appear to prefer FDA issue guidelines instead of rules. "Agendia does not support a notice of comment and rulemaking process," said Hans Herklots, head of corporate communications at Agendia. "In one way or another, LDT regulation has been the subject of debate for many years already. Most of the facts are known, and what is required now is swift action from FDA to safeguard patient safety as soon as practicable. The rulemaking process would set all stakeholders, and particularly patients, back another two to three years."
AdvaMed, an organization representing medical device and diagnostic firms, also said it supported FDA's LDT regulation through guidances rather than rulemaking.
Considerations for Labs
The main suggestions put forth by labs urged FDA to engage an advisory body of experts to establish risk-based classifications for LDTs and IVDs; collaborate with CMS to ensure that any requirements they will have to meet for FDA don't conflict with their commitments to CMS; and to establish a mechanism whereby labs can still make incremental changes to their LDTs and lab procedures without approval from the agency.
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Gutierrez provided some assurance that FDA and CMS intend to work in concert to promulgate regulations for LDTs, and noted that in some areas the two agencies are already working together. CMS looks at analytical validation under CLIA data but is challenged by the number of inspections it must perform. As a result, "it's not uncommon for CMS to ask FDA for help in looking at that data," Gutierrez said at the meeting.
In a white paper issued ahead of FDA's LDT meeting, AdvaMed proposed six principles by which to craft the agency's new regulatory framework, echoing many of the concerns aired at the meeting.
AdvaMed recommends that all clinical labs should be subject to requirements under CLIA and quality standards; FDA should oversee the safety and effectiveness of all diagnostic tests, regardless of where they are manufactured; the agency's regulatory requirements should be proportional to the risk a diagnostic test presents to public health; regulation should not hinder access to tests for rare diseases; FDA should harmonize with CMS's requirements to reduce redundancy and manage resources; and the agency should work with CMS to support "timely and adequate reimbursement" for new diagnostics.
Although AdvaMed supports FDA oversight of all tests, the group recognizes that "substantial numbers" of these tests — both LDTs and IVDs — should be exempt from FDA regulation because they represent well-established technologies used to detect familiar biomarkers. Further in support of this recommendation, AdvaMed points out that the risk of a test is tied to its frequency of use, and as such, particularly low-risk tests or tests for rare diseases should be exempt from FDA premarket submissions. "For these tests, we would instead recommend enhanced CLIA oversight and adverse event reporting," AdvaMed writes in its white paper.
The group also proposes a four-tiered risk classification system — Tier 0 for low-risk tests to Tier III for tests of high or unknown risk — which factors in whether the technology being reviewed by the agency involves a new biomarker, analyte, intended use, or algorithm; if there are predicates to the technology; if FDA has experience reviewing similar devices; whether there is sufficient scientific evidence to support the safety and effectiveness relative to the risk associated with the test; and the level of harm for patients if test results are incorrect.
Elaine Lyon, chair of the Association for Molecular Pathology's professional relations committee, advised FDA to engage the Clinical and Laboratory Standards Institute, the Centers for Disease Control and Research, and CAP to address analytical and clinical validation of LDTs.
"By working with these organizations it should be easy to do validation without the need for an additional regulatory process," Lyon said. She noted that the ability to employ different extraction methods "or an alternative but comparable real-time instrumentation" is very important for laboratories, since "purchasing a wide array of instruments or systems is not realistic or possible."
Mitch Nelles, VP of R&D and technical operations for XDx — the developer of the FDA-cleared AlloMap gene expression test — suggested that FDA do away with special 510(k) clearance requirements for additional instruments associated with an already-cleared test. For many labs this additional requirement "appears overly burdensome," Nelles said.
He suggested that FDA eliminate this requirement "as long as the new instruments demonstrate equivalent functional performance compared to the originally cleared instruments and that they have been qualified and validated to the same standards as those original instruments."
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ACLA's Mongillo urged FDA to craft a risk-based system that will still allow for the rapid market entry of tests in a public health crisis. FDA officials acknowledged that any regulatory system developed by the agency will prioritize this rapid-access pathway for tests in emergency public health situations.
Device Manufacturers Weigh In
IVD manufacturers who have invested in getting FDA approval for their tests were less sympathetic to the challenges that increased agency oversight might pose for some laboratories.
In 2005, after Agendia had launched MammaPrint in the US market but before it submitted the test to the FDA, "many in the industry told us not to bother seeking FDA clearance," Sixt said, adding that he was warned that the effort would be a "waste [of] time and money." Nevertheless, Agendia did so anyway and the test became the first IVDMIA cleared by the FDA.
Now, having taken its test through FDA, Agendia would like for the agency to require that all moderate and high-risk diagnostics clear their tests through the agency before going to market. In Sixt's view, this would not constitute an overly burdensome requirement.
"There are many who argue that FDA regulation will stifle innovation. However, with regard to commercially available clinical tests, innovations need to be done in a very controlled manner under quality system regulation design control," Sixt said. "And it works. My company is the living proof."
He reiterated that "it was straightforward and quick to clear improvements with the FDA that span technical and clinical aspects of MammaPrint."
Agendia received its first 510(k) clearance for MammaPrint in February 2007. Then in June 2007, FDA cleared RNA Retain, the stabilizing solution allowing Agendia to safely ship tumor biopsies for analysis by MammaPrint. A year later, Agilent's High Density Microarray Chip, which serves as the platform for the MammaPrint assay, received the agency's clearance.
Sixt told PGx Reporter that the cost of filing for clearance with the FDA, not including the cost of clinical trials, was around $3,800. Given this "minimal cost" for a submission to the agency, Sixt said he didn't understand why certain competitors, although they had already invested in large studies showing the clinical and analytical validity of the test, hadn't yet pursued FDA clearance.
Although Sixt did not name any specific competitors, it is well known that Genomic Health sells the most highly reimbursed "homebrew" gene expression test that gauges patients' likelihood for breast cancer recurrence and response to chemotherapy.
Genomic Health has previously said it has been in discussion with the FDA regarding Oncotype DX's regulatory status. However, the agency has never required the firm to submit the test for clearance or approval.
At the FDA meeting, Kathy Hibbs, senior VP and general counsel of Genomic Health, said that Oncotype DX has been studied in 13 trials, involving 4,000 patients. Hibbs added that since launching the test in 2004, 10,000 physicians have ordered the test for 150,000 patients.
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Genomic Health did not state any specific recommendations it supports with regard to FDA's LDT regulation, but noted that the company will contribute to comments submitted by two industry trade organizations: the Coalition for 21st Century Medicine and the American Clinical Laboratory Association.
Furthermore, in response to Agendia's comments, the firm stated in an e-mail that given the bifurcated regulatory pathway for LDTs, "to date there has not been a clear FDA path for the regulation of LDTs, and the agency has made it very clear that its review/approval is not required for these tests at this time."
Requests for comment to several other labs, device manufacturers, and industry groups were not answered, likely because many are crafting their statements on the FDA's LDT regulation. The deadline for submitting public comments is Aug. 15.
"I thought the recent FDA LDT meeting provided a good forum for various views to be expressed, and I agree with the proposed concept of using 'clinical risk' as a key element to determine the level of regulatory oversight versus using a technology-based approach," Deborah Neff, CEO of Pathwork Diagnostics, told PGx Reporter. Pathwork earlier this year received FDA clearance for its tissue-of-origin test.
"The industry is now looking to the FDA to incorporate the input from the session and establish straightforward guidelines and rules we can use to operate, so we can all understand expectations for regulatory requirements for molecular diagnostic tests," Neff said.